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Safety and Efficacy of Everolimus Treatment in Liver Transplantation for Liver Cancer

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ClinicalTrials.gov Identifier: NCT02081755
Recruitment Status : Active, not recruiting
First Posted : March 7, 2014
Last Update Posted : July 20, 2022
Information provided by (Responsible Party):
Baylor Research Institute

Brief Summary:
This study is a prospective Phase IV study to determine if the use of Everolimus results in lower liver tumor recurrence and improved patient and graft survival after liver transplant for hepatocellular carcinoma (HCC). The immunosuppressive comparators will be Everolimus and Tacrolimus therapy compared to Tacrolimus and Mycophenolic acid/Mycophenolate Mofetil/Azathioprine. Primary outcomes data is disease free survival (the time from randomization to HCC recurrence or death). Secondary outcomes are rate of recurrence of Hepatitis C, problems related to wound healing, hernia repair within the first 12 months, hepatic arterial thrombosis, renal function, acute cellular rejection, post-transplant diabetes, hypertension, and hyperlipidemia.

Condition or disease Intervention/treatment Phase
Carcinoma, Hepatocellular Drug: Everolimus Drug: Tacrolimus Drug: Myfortic Drug: CellCept Drug: Imuran Phase 4

Detailed Description:

The study population will consist of approximately 336 patients (224 Everolimus and Tacrolimus and 112 Tacrolimus and Mycophenolic acid/Mycophenolate Mofetil/Azathioprine). Initial screening criteria will include the presence of hepatocellular carcinoma in patients 18 years or older who are candidates to receive a primary orthotopic liver transplant (from deceased or living donor). Within 7 - 12 days post-transplant, patients will be re-evaluated for eligibility for randomization. The criteria include: pre-transplant imaging that shows HCC disease exceeding Milan criteria; pathology review for tumor burden and/or presence of microvascular invasion; AFP >200IU/mL; pre-transplant ablation or resection with HCC recurrence; progression or new tumors; evaluation to rule out any hepatic vessel complication.

Subjects will remain in study treatment until Month 12 at which time the subject and investigator will determine the preferred immunosuppressive regimen. Subjects will be followed for an additional 24 months for outcome data as described above.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 336 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A 36 Month Multi-center, Open Label, Randomized, Comparator Study to Evaluate the Efficacy and Safety of Everolimus Immunosuppression Treatment in Liver Transplantation for Hepatocellular Carcinoma Exceeding Milan Criteria
Actual Study Start Date : March 2014
Estimated Primary Completion Date : January 2023
Estimated Study Completion Date : January 2023

Resource links provided by the National Library of Medicine

Arm Intervention/treatment
Experimental: Everolimus and Tacrolimus
Everolimus Dosing: 1.5 mg BID (3.0 mg/day) Tacrolimus Dosing: 0.05 mg/kg BID
Drug: Everolimus
Everolimus Dosing: 1.5 mg BID (3.0 mg/day) for 12 months
Other Names:
  • Zortress
  • Afinitor

Drug: Tacrolimus
Tacrolimus Dosing: 0.05 mg/kg BID for 12 months
Other Name: Prograf

Active Comparator: Tacrolimus and Myfortic or CellCept or Imuran
Myfortic: 360 mg to 1080 mg BID OR CellCept: 500 mg to 1500 mg BID OR Imuran: 0.5mk/kg to 2mg/kg QD AND Tacrolimus Dosing: 0.05 mg/kg BID
Drug: Tacrolimus
Tacrolimus Dosing: 0.05 mg/kg BID for 12 months
Other Name: Prograf

Drug: Myfortic
Myfortic®: 360 mg to 1080 mg BID for 12 months
Other Name: Mycophenolic Acid

Drug: CellCept
CellCept: 500 mg to 1500 mg BID for 12 months
Other Name: Mycophenolate Mofetil

Drug: Imuran
0.5 mg/kg to 2 mg/kg QD for 12 months
Other Name: Azathioprine

Primary Outcome Measures :
  1. Disease free survival (DFS) defined as the time from randomization to the time of tumor recurrence or death, whichever occurs first. [ Time Frame: Through Month 36 ]

Secondary Outcome Measures :
  1. Tumor recurrence sites [ Time Frame: Through Month 36 ]
  2. Hepatitis C recurrence rate [ Time Frame: Through Month 36 ]
  3. Renal function [ Time Frame: Through Month 36 ]
  4. Acute cellular rejection [ Time Frame: Through Month 36 ]
  5. Post-transplant diabetes [ Time Frame: Through Month 36 ]
  6. Hypertension [ Time Frame: Through Month 36 ]
  7. Hyperlipidemia [ Time Frame: Through Month 36 ]
  8. Wound healing and associated risk factors [ Time Frame: Through Month 36 ]
  9. Hernia repair [ Time Frame: Through Month 36 ]
  10. Hepatic arterial thrombosis [ Time Frame: Through Month 36 ]

Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

Screening Inclusion Criteria:

  • Have a diagnosis of hepatocellular carcinoma (HCC) and high risk for HCC recurrence
  • Able to provide written informed consent
  • Male and female patients of any race, 18 years or older
  • De novo recipients of a primary orthotopic liver transplant from a deceased or living donor
  • Patients willing to comply with study requirements
  • Women of child-bearing potential (WOCBP) must agree to use an effective method(s) of contraception during treatment and during the post treatment follow-up period

Screening Exclusion Criteria:

  • Past or present malignancy within the last 5 years.
  • Severe infection considered by the local site investigator to be unsafe for study participation.
  • Use of other investigational drugs at the time of screening or within the last 30 days.
  • Patients scheduled for a combined transplant (such as liver-kidney), or having a previous solid organ, bone marrow, or autologous islet cell transplant.
  • Recipients of donor/recipient ABO incompatible grafts.
  • Recipients of organs from human immunodeficiency virus (HIV) or HBsAg positive donors.
  • Macrovascular tumor invasion.
  • Proteinuria greater than 2 grams/24 hours.
  • Conditions which can result in impaired absorption, distribution, metabolism or excretion of the study treatment.
  • Patients with non-infectious pneumonitis.
  • Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a female after conception and until the termination of gestation, confirmed by a positive human chorionic gonadotropin (hCG) laboratory test.
  • Women of child-bearing potential (WOCBP) not practicing an effective method(s) of contraception.
  • Patients who receive sirolimus (Rapamune®) as part of their transplant immunosuppression regimen

Randomization Screening Inclusion Criteria :

- For patients with a history of any hepatic vessel thrombosis, occlusion, stent placement, or major revision of liver vessels, must have a Doppler ultrasound prior to randomization to rule out any hepatic vessel complication, including hepatic arterial thrombosis (HAT).

Randomization Exclusion Criteria:

  • Patients who receive sirolimus (Rapamune) any time prior to randomization will be withdrawn from the study.
  • Patients who develop clinically significant systemic infections requiring active use of IV antibiotics any time prior to randomization.
  • Wound healing problem, per Investigator's assessment, that would make the patient ineligible for study randomization
  • Confirmed presence of a thrombosis in a major hepatic artery(s), major hepatic vein(s), portal vein or inferior vena cava via Doppler ultrasound or other imaging obtained prior to randomization.
  • Proteinuria greater than 2 grams/24 hours.
  • Consideration by the investigator, for any reason, that the subject is an unsuitable candidate to receive everolimus or be randomized into the study.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02081755

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United States, California
University of California at San Francisco
San Francisco, California, United States, 94143
United States, Illinois
Northwestern University School of Medicine
Chicago, Illinois, United States, 60611
United States, Kansas
University of Kansas Medical Center
Kansas City, Kansas, United States, 66160
United States, Minnesota
Mayo Clinic
Rochester, Minnesota, United States, 55905
United States, Missouri
Washington University School of Medicine
Saint Louis, Missouri, United States, 63110
United States, New York
Mount Sinai Medical Center
New York, New York, United States, 10029
United States, Pennsylvania
University of Pennsylvania
Philadelphia, Pennsylvania, United States, 19104
United States, Tennessee
University of Tennessee- Methodist University Hospital
Memphis, Tennessee, United States, 38104
United States, Texas
Baylor University Medical Center
Dallas, Texas, United States, 75246
Sponsors and Collaborators
Baylor Research Institute
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Principal Investigator: Goran Klintmalm, MD, PhD Baylor Health Care System
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Responsible Party: Baylor Research Institute
ClinicalTrials.gov Identifier: NCT02081755    
Other Study ID Numbers: 013-307
First Posted: March 7, 2014    Key Record Dates
Last Update Posted: July 20, 2022
Last Verified: July 2022
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No
Keywords provided by Baylor Research Institute:
Immunosuppressive Agents
Liver Transplantation
Additional relevant MeSH terms:
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Carcinoma, Hepatocellular
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Liver Neoplasms
Digestive System Neoplasms
Neoplasms by Site
Digestive System Diseases
Liver Diseases
Mycophenolic Acid
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Calcineurin Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Antibiotics, Antineoplastic
Antibiotics, Antitubercular
Antitubercular Agents
Anti-Bacterial Agents
Anti-Infective Agents
Antimetabolites, Antineoplastic
Antirheumatic Agents